It is known that cutis, because of the particular functions it has, is structured in a particular way and is substantially comprised of two superimposed layers, namely, the underlying derma and the epidermis forming the external surface of cutis.
As epidermis is devoid of blood vessels, even if it must carry out many of the most remarkable functions of the skin, such as the protective, secretive, thermoregulating, respiratory functions, and so on, metabolic impairments often occur, affecting its appearance and jeopardizing its functions, which may often be serious.
It is also known that hair, as the essential Dart of the human piliferous apparatus, is planted in epidermis, so that it also shares in a very considerable way its vicissitudes and deficiencies. Therefore, loss of hair is a more and more frequent phenomenon both in men and in women, also in situations which are not typically pathological. The multifactorial aetiogenesis of such hair loss, which may be related to stress, atmospheric pollution, emotional factors, use of strongly detergent shampoos, for example, is always related to a morphological alteration in the connective tissue surrounding the hair bulb which is determined, inter alia, by the decrease of specific acidic mucopolysaccharides such as heparin, hyaluronic acid, and A, B, C, chondroitinsulfates in the connective tissue itself, with attendant dehydration, aging of the tissue, and dekeratinization, together with fragility and poor elasticity of the hair, and finally sclerosis and death of the hair bulb.
Hair growth is influenced by hormones for at least two major evolutionary reasons. One is so that the heat-conserving pelage can be changed to match the season. The other is so that the growth of sexual hair and production of scent from the associated glands can be restricted to the adult period.
It is possible that remnants of the first function are detectable in humans, for there are some indications of seasonal change, and there is clear evidence that the thyroid hormone has a profound effect on hair growth. Moreover, post-partum hair loss appears to be a consequence of hormonal changes in pregnancy and may well be analogous to the moult which follows parturition in some other mammals.
However, of paramount importance is the role of androgens in promoting growth of the beard in males, and of the pubic and axillary hair in both sexes, as is the paradoxical fact that hereditary male pattern baldness is androgen-dependent. Testosterone is carried in the human plasma attached to sex hormone binding globulin, and only about one percent is free to enter cells and become bound to intracellular receptors. There is some question as to whether the response of hair follicles, like that of the prostate, requires 5 .alpha.-reduction of the androgen, and whether the critical factors in male pattern alopecia, female-diffuse alopecia, and hirsutism are abnormally high plasma androgen, low sex hormone binding globulin, enhanced 5 .alpha.-reductase, enhanced binding by the intracellular receptor, or some other yet undiscovered mechanism.
Androgens are mainly produced in steroid producing glands. Additionally, they are formed in the body periphery from precursors such as DHIA and androstendione. In the ovaries they play an important role as biosynthetic intermediates for the synthesis of estrogens as well as for folliculogenesis. If this o process is disturbed, ovarian androgen secretion often is increased. Under clinical conditions, glandular androgen production is calculated best by measuring the steroid output in the effluent of the adrenals and gonads after catheterization of the glandular venes. Functional tests are less informative, and can occasionally be misleading. On the basis of androgen measurements in the glandular effluents of 80 androgenized women, increased androgen secretion comes in about half of the cases either form the ovaries or the adrenal glands and in the other half, from both glands.
Androgens in the blood are predominantly bound to sex hormone binding globulin and albumin. Just 0.5-2.0% of blood testosterone is present in the free, unbound form. Only this unbound blood androgen is believed to be biologically active. Androgenic alopecia is often associated with other signs of andro-genization. It is an obligatory symptom in severe virilism due to a massive increase in androgen production. In these cases, ablative surgery or suppression of the androgen excess by other means, such as by corticoids, rather than treatment by antiandrogens are the methods of first choice.
Male hormones affect human sebaceous glands and hair follicles. Skin conditions, such as male-pattern baldness, ache, hirsutism, and seborrhea, are attributed to over-androgenicity.
There are dramatic changes in hair growth at puberty which are selectively mediated by testosterone or by dihydrotestosterone. The characteristic increase of hairiness at puberty is not due to the formation of new follicles, as there is no neogenesis of hair follicles in the human. Rather, the increased hairiness is due to the conversion of small terminal follicles to large terminal follicles. In the axilla and lower public triangle, this conversion is mediated by testosterone or androstenedione. In all other regions, this conversion is mediated by dihydrotestosterone. Paradoxically, dihydrotestosterone also mediates the reverse process, namely, the miniaturization of large terminal follicles into small terminal follicles. Such physiological miniaturization occurs with the reshaping of the frontal hairline from a straight hairline to an M-shaped hairline. This occurs in all men and in the majority of women. In androgenic alopecia, the miniaturization process extends to include all genetically marked follicles. In the male, this may include all except the hair follicles along the peripheral margins of the scalp. In the female, the genetically marked follicles are scattered diffusely over the scalp with preservation of the frontal hairline.
The importance of the skin as an androgen target organ and the influence of androgens on hair growth are most convincingly demonstrated by two forms of male pseudohermaphroditism, testicular feminization and 5-.alpha.-reductase deficiency, in which the influence of androgens is lacking to different degrees.
It has been found that the administration of testosterone to the AGA mouse resulted in a patterned hair loss beginning at the dorsal head region and extending posteriorly towards the mid-dorsum over a three month period. Hair loss was characterized by a very small decrease in the growth phase (anagen), and a markedly prolonged duration of the resting phase (telogen). Alopecia in this model can be prevented by the administration of potent 5.alpha.-reductase and androgen receptor blocking agents, such as progesterone, cyproterone acetate, or spironolactone. Various vasodilating drugs, which are reported to produce hypertrichosis as a side effect when given to humans, were tested in testosterone-treated AGA mice by oral administration at a dose of 10 mg/kg. Minoxidil and diazoxide inhibited the testosterone induced alopecia at concentrations of 2% and 5%.
It is known that the female sexual hormones antagonize the masculine hormones at the peripheral target androgenosensible tissue. Munteanu et al. attempted to use progesterone in the local treatment of seborrheic alopecia. Progesterone was chosen because it is a strong inhibitor of the testosterone-blocking 5.alpha.-reductase and in this manner hinders the reduction of testosterone into 5.alpha.-dihydrotestosterone that produces a gene depression and consequently a follicle atrophy of the hairs of the head. In this way, the anagenesis phase of the hair is prolonged, in which the androgenetic alopecia is very short. Progesterones resorbed by the skin are concentrated within the hair follicle. No hormonal disorders and no androgenic effects were observed.
The most common form of hair loss is male-pattern alopecia, in which hair anagen (hair growth stage) gradually shortens and regenerated hair becomes thinner and shorter generation by generation in the temporal and parietal regions. It has been well established that such a phenomenon cannot occur without androgen.
The pathology of male-pattern alopecia is that the effect of androgen on the scalp expands sebaceous crypts and simultaneously shortens the hair cycle, namely, the cycle of hair life. In other words, alopecia is a phenomenon where a person's hair, which was originally long and thick, becomes thinner and shorter with every hair cycle.
It is known that, among androgens presenting the above effect on local dermal areas, 5 .alpha.-dihydrotestosterone (5 .alpha.-DHT) plays a principal role, and that 5.alpha.-DHT is produced through conversion from testosterone with the assistance of an enzyme, 5.alpha.-reductase, in sebaceous crypts or dermis fibroblasts.
Previously, in order to prevent aging of cutis and, particularly, hair loss, a number of different therapies have been proposed, including the local use of degreasing, rubefacient and vasodilating agents, polyvitaminic compositions, and vegetable extracts of different kinds, as well as mucopolysaccharide extracts with unspecified compositions and activity (with particular reference to the anticoagulant and lipasemic activities, which are closely correlated and interdependent activities) alone or in combination. However, none of these compounds has ever faced in a rational way, and consequently solved, the problem of physiological hydration of cutis and of the tissue surrounding the hair bulb which is an essential condition for the vitality of the bulb itself and thus of the hair.
Even if the use of sulfomucopolysaccharides, which notoriously possess hydrophilic properties, is already known, it is likewise known that these compounds usually are not substantially absorbed through cutis.